Patient-Reported Outcome Measures following Coblation Nucleoplasty for Cervical Discogenic Dizziness.

BACKGROUND: There is little research in the literature comparing the efficacy of coblation nucleoplasty with conservative treatment in the treatment of cervical discogenic dizziness and reporting the achieved rate of minimal clinically important differences (MCID) and patient acceptable symptom state (PASS) after surgery. This retrospective study aims to explore the patient-reported outcome measures (PROM) following coblation nucleoplasty for cervical discogenic dizziness and to compare the therapeutic effect of coblation nucleoplasty with prolonged conservative treatment. METHODS: Sixty-one patients with cervical discogenic dizziness and a positive intradiscal diagnostic test eligible for single-level cervical coblation nucleoplasty were included in the study. Among these 61 patients, 40 patients underwent cervical coblation nucleoplasty, while the remaining 21 patients refused surgery and received continued conservative treatment. The primary PROMs were the intensity and frequency of dizziness and secondary PROMs were related to the neck disability index (NDI) and visual analog scale (VAS) for neck pain (VAS-neck) during a 12-month follow-up period. Moreover, the achieved rate of MCID and PASS in both groups was assessed 12 months after surgery. RESULTS: Dizziness intensity, dizziness frequency, VAS-neck score, and NDI score were significantly improved from the baseline at all follow-up time points in both treatment groups, except for showing no significant improvement in dizziness frequency in the conservative treatment group at 6 and 12 months after surgery. However, at each follow-up time point, the above indexes were lower in the surgery group than in the conservative treatment group. In addition, the achieved rates for PASS and MCID in all indexes in the surgery group were significantly higher than those in the conservative treatment group at 12 months after surgery. CONCLUSIONS: Cervical coblation nucleoplasty significantly improved the intensity and frequency of dizziness, neck pain, and NDI in patients with cervical discogenic dizziness, and the results were superior to those from prolonged conservative treatment. Meanwhile, cervical coblation nucleoplasty is a good choice for patients with chronic neck pain and refractory cervical discogenic dizziness who have not demonstrated the indications for open surgery and have not responded well to conservative treatment.

Anterior Cervical Decompression and Fusion Surgery for Cervical Spondylosis with Concomitant Tinnitus: A Multicenter Prospective Cohort Study.

OBJECTIVE: Cervical spondylosis is often accompanied by tinnitus. Up to now, there is a lack of large samples and prospective studies to investigate the effect of anterior cervical decompression and fusion (ACDF) on tinnitus associate with cervical spondylosis. To this end, we performed a prospective cohort study to assess the effectiveness of ACDF on the relief of tinnitus. METHODS: This was a multicenter, prospective, cohort clinical study. Between August 2017 and August 2018, 174 patients with cervical spondylosis accompanied by tinnitus were enrolled, with a follow-up of 12 months. Among the 174 patients, 142 received anterior cervical surgery (surgery group) and 32 received conservative treatment (conservative group). The primary end point was the mean change in scores on the tinnitus functional index (TFI). The secondary end points included tinnitus loudness, modified Japanese orthopaedic association scores (mJOA) for spinal cord function, and visual analogue scale (VAS) for neck pain. All the above indexes were measured before treatments and at 1, 3, 6, and 12 months after treatments. One-way analysis of variance and paired samples t-test was adopted for statistical analysis. RESULTS: The TFI score was reduced immediately after cervical decompression surgery (from 54.7 ± 15.6 to 32.3 ± 12.5, P < 0.001) and this was sustained at 12 months (P < 0.001). The TFI score of the conservative group also decreased (from 53.9 ± 16.8 to 45.2 ± 13.6, P < 0.001), but the effect was not maintained at 12 months (P = 0.069). There was a significant improvement in tinnitus loudness (from 5.2 ± 1.6 to 2.6 ± 1.9, P < 0.001), mJOA (from 12.0 ± 1.6 to 14.2 ± 1.6, P < 0.001), and VAS for neck pain (from 58.5 ± 9.6 to 22.0 ± 16.4, P < 0.001) in the surgical group. Improvements in the surgical group were statistically significantly greater than that in the conservative group (P < 0.001). CONCLUSION: This study indicates that anterior cervical surgery can relieve tinnitus in patients with cervical spondylosis and that tinnitus is an accompanying manifestation of cervical spondylosis.

Anterior cervical decompression and fusion surgery for cervicogenic headache: A multicenter prospective cohort study.

Background: Cervicogenic headache (CEH) has long been recognized as a referred pain deriving from pathological changes in the upper cervical nerves. However, previous clinical studies found that anterior lower cervical discectomy for the treatment of cervical myelopathy and/or radiculopathy can also help relieve associated headaches. To date, there is still a lack of large sample and prospective study to investigate the effect of anterior cervical decompression and fusion (ACDF) on CEH associated with cervical spondylosis. Methods: A total of 656 patients with cervical radiculopathy and/or myelopathy were enrolled in three spinal centers. Among them, 221 patients who were diagnosed with CEH were collected in this study, and 204 completed a 1-year follow-up. The primary endpoint was headache intensity during a 12-month follow-up period measured by the numeric pain rating scale (NPRS). The secondary outcome measures included headache frequency, headache duration, and the neck disability index (NDI). Results: Among all 204 patients with CEH who completed a 1-year follow-up, 166 received anterior cervical surgery (surgery group) and 38 received conservative treatment (conservative group). There were statistically significant lower NPRS in the surgical group during follow-up. Between-group differences showed that NPRS in the surgery group was significantly greater improvement at 1 month (2.8, 95% CI: 2.0, 3.6), 3 months (2.6, 95% CI: 1.8, 3.4), 6 months (2.4, 95% CI: 1.6, 3.2), and 12 months (1.5, 95% CI: 0.7, 2.4) (p < 0.05 for all). There were statistically significant lower NDI, less frequent headaches, and lower headache duration in the surgery group during follow-up (p < 0.05 for all). Conclusion: This study indicates that ACDF can effectively relieve CEH associated with cervical myelopathy and/or radiculopathy.

Cytochrome P450-2D6: A novel biomarker in liver cancer health disparity.

Liver cancer morbidity and mortality rates differ among ethnic groups. In the United States, the burden of liver cancer in Asian Americans (AS) is higher compared to Caucasian Americans (CA). Research on liver cancer health disparities has mainly focused on environmental and socioeconomic factors yet has ignored the genotypic differences among various racial/ethnic groups. This lack of molecular level understanding has hindered the development of personalized medical approaches for liver cancer treatment. To understand the genetic heterogeneity of liver cancer between AS and CA, we performed a systematic analysis of RNA-seq data of AS and CA patients from The Cancer Genome Atlas (TCGA). We used four differential gene expression analysis packages; DESeq2, limma, edgeR, and Superdelta2, to identify the differentially expressed genes. Our analysis identified cytochrome P450-2D6 enzyme (CYP2D6) as the gene with the greatest differential expression with higher levels in AS compared to CA. To scrutinize the underlying mechanism of CYP2D6, Ingenuity Pathway Analysis (IPA) and Cytoscape were conducted and found hepatocyte nuclear factor-4α (HNF4A) and interleukin-6 (IL6) in direct association with CYP2D6. IL6 is downregulated in AS compared to CA, while HNF4A is not significantly different. Herein, we report that CYP2D6 may serve as a putative biomarker in liver cancer health disparities. Its negative association with IL6 proclaims an intricate relationship between CYP2D6 and inflammation in the ethnic differences seen in AS and CA liver cancer patients. The goal of the present study was to understand how genetic factors may contribute to the interethnic variability of liver cancer prevalence and outcomes in AS and CA patients. Identifying ethnic-specific genes may help ameliorate detection, diagnosis, surveillance, and treatments of liver cancer, as well as reduce disease-related incidence and mortality rates in the vulnerable population.

Anterior Cervical Surgery for the Treatment of Cervicogenic Headache Caused by Cervical Spondylosis.

STUDY DESIGN: Retrospective study. OBJECTIVE: To report the efficacy of anterior cervical surgery for the relief of cervicogenic headache (CEH) caused by cervical spondylosis. METHODS: From January 2014 to December 2016, a total of 166 cases of cervical radiculopathy and/or myelopathy received anterior cervical decompression and fusion (ACDF) in our institution, among which 50 cases (mean age 44.7 years) were accompanied by CEH and followed up at 3, 6, 12, and 24 months postoperatively, respectively. Neck pain and headache scores according to neck disability index (NDI) were documented for all patients at regular intervals. The results measured at different follow-up time point were compared statistically. RESULTS: All 50 patients reported neck pain and headache at the same time before surgery. The average NDIs for neck pain before and after surgery were 2.86 (95% CI: 2.7-3.0) preoperatively, 0.98 (95% CI: 0.8-1.1) at 3 months, 0.68 (95% CI: 0.5-0.9) at 6 months, 0.62 (95% CI: 0.5-0.8) at 12 months, and 0.60 (95% CI: 0.4-0.8) at 24 months postoperatively, respectively. The average NDIs for CEH before and after surgery were 2.32 (95% CI: 2.2-2.5) preoperatively, 0.62 (95% CI: 0.5-0.8) at 3 months, 0.60 (95% CI: 0.4-0.8) at 6 months, 0.56 (95% CI: 0.4-0.7) at 12 months, and 0.50 (95% CI: 0.3-0.7) at 24 months postoperatively, respectively. The neck pain and headache improved in all cases and the NDI score of neck pain or headache at each follow-up point after surgery was significantly different from that before surgery (P <0.001). The simple correlation analysis between neck pain and headache was performed, and the Pearson coefficient r was 0.71, indicating a positive correlation between neck pain NDI and headache NDI. No serious surgical complications were found. CONCLUSION: Our study suggests that patients with cervical spondylosis complicated with CEH are always accompanied by neck pain. ACDF can not only relieve neck pain but also improve the accompanying CEH.

Genetic factors associated with cancer racial disparity - an integrative study across twenty-one cancer types.

It is well known that different racial groups have significantly different incidence and mortality rates for certain cancers. It has been suggested that biological factors play a major role in these cancer racial disparities. Previous studies on the biological factors contributing to cancer racial disparity have generated a very large number of candidate factors, although there is modest agreement among the results of the different studies. Here, we performed an integrative analysis using genomic data of 21 cancer types from TCGA, GTEx, and the 1000 Genomes Project to identify biological factors contributing to racial disparity in cancer. We also built a companion website with additional results for cancer researchers to freely mine. Our study identified genes, gene families, and pathways displaying similar differential expression patterns between different racial groups across multiple cancer types. Among them, XKR9 gene expression was found to be significantly associated with overall survival for all cancers combined as well as for several individual cancers. Our results point to the interesting hypothesis that XKR9 could be a novel drug target for cancer immunotherapy. Bayesian network modeling showed that XKR9 is linked to important cancer-related genes, including FOXM1, cyclin B1, and RB1CC1 (RB1 regulator). In addition, metabolic pathways, neural signaling pathways, and several cancer-related gene families were found to be significantly associated with cancer racial disparities for multiple cancer types. Single nucleotide polymorphisms (SNPs) discovered through integrating data from the TCGA, GTEx, and 1000 Genomes databases provide biologists the opportunity to test highly promising, targeted hypotheses to gain a deeper understanding of the genetic drivers of cancer racial disparity and cancer biology in general.

The novel BET-CBP/p300 dual inhibitor NEO2734 is active in SPOP mutant and wild-type prostate cancer.

CULLIN3-based E3 ubiquitin ligase substrate-binding adaptor gene SPOP is frequently mutated in prostate cancer (PCa). PCa harboring SPOP hotspot mutants (e.g., F133V) are resistant to BET inhibitors because of aberrant elevation of BET proteins. Here, we identified a previously unrecognized mutation Q165P at the edge of SPOP MATH domain in primary and metastatic PCa of a patient. The Q165P mutation causes structural changes in the MATH domain and impairs SPOP dimerization and substrate degradation. Different from F133V hotspot mutant tumors, Q165P mutant patient-derived xenografts (PDXs) and organoids were modestly sensitive to the BET inhibitor JQ1. Accordingly, protein levels of AR, BRD4 and downstream effectors such as RAC1 and phosphorylated AKT were not robustly elevated in Q165P mutant cells as in F133V mutant cells. However, NEO2734, a novel dual inhibitor of BET and CBP/p300, is active in both hotspot mutant (F133V) and non-hotspot mutant (Q165P) PCa cells in vitro and in vivo. These data provide a strong rationale to clinically investigate the anti-cancer efficacy of NEO2734 in SPOP-mutated PCa patients.

Cervical Intervertebral Disc Degeneration Contributes to Dizziness: A Clinical and Immunohistochemical Study.

OBJECTIVES: Dizziness often happens in patients with chronic neck pain with only cervical disc degeneration but without cervical radiculopathy or myelopathy. We prospectively selected a series of patients who showed cervical disc degeneration with concomitant chronic neck pain and intractable dizziness who did not respond to conservative treatment to test a new diagnostic method for this dizziness, to analyze the results of anterior cervical discectomy and fusion (ACDF) surgery based on the test, and to explore its pathogenesis. METHODS: Seventy-seven patients who had a transient neck pain and dizziness relief after injection of bupivacaine into a suspected disc were included in the study. In total, 52 underwent ACDF as surgery group, and 25 refused surgery and accepted conservative treatments as conservative group from June, 2015 to October, 2016 with subsequent follow-up to 1 year. The outcomes were visual analogue scale for neck pain, Neck Disability Index, and intensity and frequency of dizziness. During ACDF, the 72 specimens of degenerative cervical discs were collected to determine the innervation in degenerative cervical discs immunohistochemically. RESULTS: After surgery, the patients experienced a significant reduction in neck pain and dizziness. Symptomatic relief in surgery group was obviously better than conservative group at each time point of follow-up (P = 0.001). Ruffini corpuscles and substance P-positive free nerve fibers were obviously increased in the number and deeply ingrown into the inner degenerative cervical discs. CONCLUSIONS: Current clinical and immunohistochemical studies strongly suggest that chronic neck pain and intractable dizziness in this series of patients stem from the degenerative cervical discs.

Cervical Decompression Surgery for Cervical Spondylotic Myelopathy and Concomitant Hypertension: A Multicenter Prospective Cohort Study.

STUDY DESIGN: We performed decompression surgery or conservative treatments on 135 cervical spondylotic myelopathy (CSM) patients with concomitant hypertension and did follow-up assessments up to 1 year to examine the change of blood pressure, spinal cord function, and cervical pain. OBJECTIVE: The aim of this study was to determine whether concomitant hypertension is relieved after decompression surgery, and whether it is related to the improvement of spinal cord function or cervical pain. SUMMARY OF BACKGROUND DATA: In clinical practice, we often found that some patients with CSM have concomitant hypertension. Interestingly, after CSM was treated successfully by decompression surgery, some patients' high blood pressure returned to normal range even without oral medications. METHODS: We enrolled 135 CSM patients with hypertension, 103 of whom received decompression surgery, and remaining 32 patients accepted conservative treatments. We did follow-up assessments at 3, 6, and 12 months. The primary endpoints were changes of blood pressure, and secondary endpoints were changes of modified Japanese Orthopedic Association (mJOA) score and cervical pain visual analogue scale (VAS). Spearman correlation coefficients were calculated between changes in systolic blood pressure (SBP) and mJOA scores, VAS scores. RESULTS: In patients with decompression surgery, the significant decrease in both SBP and diastolic blood pressure (DBP) that was seen 3 months and sustained through subsequent visit at 12 months. Paired-samples t test showed that both SBP and DBP were significantly lower than baseline blood pressure at all time points after procedure (P < 0.001). Significant correlation was found between the improvement rates of mJOA score and changes in SBP (r = -0.579, P < 0.001). But the correlation between changes in VAS score and changes in SBP was not significant (r = 0.58, P = 0.571). CONCLUSION: Cervical decompression surgery could reduce concomitant high blood pressure in CSM patients, indicating a significant association between the decrease in blood pressure and the improvement of spinal cord function. LEVEL OF EVIDENCE: 2.

Disorder-to-Order Transition of an Active-Site Loop Mediates the Allosteric Activation of Sortase A.

Intrinsically disordered proteins and intrinsically disordered regions are implicated in many biological functions and associated with many diseases, but their conformational characterizations are challenging. The disordered ß6/ß7 loop of Staphylococcus aureus sortase A is involved in the binding of both sorting signals and calcium. Calcium binding allosterically activates the enzyme, but the detailed mechanism has been unclear. Here we adapted the replica exchange with solute tempering method to sample the conformations of the ß6/ß7 loop, in apo form and in three liganded forms (bound with a sorting signal or calcium or both). The extensive molecular dynamics simulations yield atomic details of the disordered-to-order transition of the loop and suggest a mechanism for allosteric activation: calcium binding results in partial closure and ordering of the loop, thereby leading to preorganization of the binding pocket for the sorting signal. The approach has general applicability to the study of intrinsically disordered regions.

Truncated ERG Oncoproteins from TMPRSS2-ERG Fusions Are Resistant to SPOP-Mediated Proteasome Degradation.

SPOP mutations and TMPRSS2-ERG rearrangements occur collectively in up to 65% of human prostate cancers. Although the two events are mutually exclusive, it is unclear whether they are functionally interrelated. Here, we demonstrate that SPOP, functioning as an E3 ubiquitin ligase substrate-binding protein, promotes ubiquitination and proteasome degradation of wild-type ERG by recognizing a degron motif at the N terminus of ERG. Prostate cancer-associated SPOP mutations abrogate the SPOP-mediated degradation function on the ERG oncoprotein. Conversely, the majority of TMPRSS2-ERG fusions encode N-terminal-truncated ERG proteins that are resistant to the SPOP-mediated degradation because of degron impairment. Our findings reveal degradation resistance as a previously uncharacterized mechanism that contributes to elevation of truncated ERG proteins in prostate cancer. They also suggest that overcoming ERG resistance to SPOP-mediated degradation represents a viable strategy for treatment of prostate cancers expressing either mutated SPOP or truncated ERG.

Surgical Management of 3-Level Lumbar Spondylolyses.

Three-level lumbar spondylolyses are extremely rare. So far, only 11 cases were reported in the literature. Treatment of multilevel spondylolyses has not been consistent. Conservative treatment is commonly considered first in most patients, but those who remain symptomatic may benefit from operative treatment. We report here 3 cases of 3-level lumbar spondylolyses that were treated successfully with direct isthmic repair in 2 cases and a combined surgery of isthmic repair and interbody fusion in 1 case. Our clinical results indicated that direct defect repair using the screw-hook technique is a simple and safe procedure for the motion segment with normal disc. If the involved disc shows degenerative change, fusion surgery should be consideredSurgical treatment of multilevel spondylolyses varies between fusion, direct isthmic repair, and combined management associating 2 procedures at different levels. The success of management of the 3 patients with 3-level spondylolyses depends on the choice of appropriate treatment for every patient.

Hemolymphangioma of the waist: A case report and review of the literature.

Hemolymphangioma is a malformation of the lymphatic and blood vessels. To the best of our knowledge, only a limited number of hemolymphangioma cases have been reported in the literature thus far, with no cases developed in the waist region. The present study reported the case of a 17-year-old male patient with hemolymphangioma growing on the waist, presented with back pain for four months. Upon physical examination, the lesion was identified to be oval in shape, soft and compressible, with mild tenderness. No abnormalities were detected in the results of laboratory examinations. However, a magnetic resonance imaging (MRI) scan revealed a tumor with low signal intensity on T1-weighted imaging (WI) and high signal intensity on T2-WI. The mass was successfully removed during surgery. During the seven-month follow-up period, the patient was asymptomatic with no evidence of recurrence. The present study discussed the imaging findings and pathological features of this uncommon case and reviewed the relevant literature.

Human umbilical cord mesenchymal stem cell transplantation for the treatment of chronic discogenic low back pain.

BACKGROUND: Chronic low back pain is one of the major causes of disability and thus has a major socioeconomic impact. Intervertebral disc degeneration is the main cause of chronic low back pain. Treatment for chronic discogenic low back pain has traditionally been limited to either conservative management or surgical fusion. If conservative treatment fails, then surgical fusion is commonly considered. Current treatments are limited to treat the symptoms and not the underlying biologic alterations of the disc. OBJECTIVE: Human umbilical cord tissue-derived mesenchymal stem cells (HUC-MSCs) contain stem cells and possess the ability to regenerate degenerative discs. Based on the results of previous in vitro and animal experiments, we conducted a preliminary study to test the feasibility and safety and to obtain an early indication for the therapeutic value of HUC-MSC transplantation in patients with chronic discogenic low back pain. STUDY DESIGN: This is the first study involving treatment of chronic low back pain using HUC-MSC transplantation. SETTING: The study was performed at a spine center in China. METHODS: Two patients with chronic discogenic low back pain were treated with HUC-MSC transplantation. An 11-point visual analog scale (VAS, 0-10) and Oswestry Disability Index (ODI, 0-100) were used to assess the back pain symptoms and the lumbar function, respectively. RESULTS: After transplantation, the pain and function improved immediately in the 2 patients. The VAS and ODI scores decreased obviously during a 2-year follow-up period. LIMITATIONS: The shortcoming of this study is that it is a preliminary study with only 2 patients. CONCLUSION: The clinical outcomes indicated that HUC-MSC transplantation is a favorable alternative method for the treatment of chronic discogenic low back pain.

Design rules for selective binding of nuclear localization signals to minor site of importin α.

Selectivity is a critical issue in molecular recognition. However, design rules that underlie selectivity are often not well understood. Here, we studied five classical nuclear localization signals (NLSs) that contain the motif KRx(W/F/Y)xxAF and selectively bind to the minor site of importin α. The selectivity for the minor site is dissected by building structural models for the NLS-importin α complexes and analyzing the positive design and negative design in the NLSs. In our models, the KR residues of the motif occupy the P1' and P2' pockets of importin α, respectively, forming hydrogen-bonding and cation-π interactions. The aromatic residue at the P4' position plays dual roles in the selectivity for the minor site: by forming π-stacking with W357 of importin α to reinforce the minor-site binding; and by clashing with the P5 pocket in the major binding site. The F residue at the P8' position occupies a deep pocket, providing additional stabilization. The P7' position sits on a saddle next to the P8' pocket and hence requires a small residue; the A residue fulfills this requirement. The principal ideas behind these blind predictions turn out to be correct in an evaluation against subsequently available X-ray structures for the NLS-importin α complexes, but some details are incorrect. These results illustrate that the selectivity for the minor site can be achieved via a variety of design rules.

Molecular structure of RADA16-I designer self-assembling peptide nanofibers.

The designer self-assembling peptide RADA16-I forms nanofiber matrices which have shown great promise for regenerative medicine and three-dimensional cell culture. The RADA16-I amino acid sequence has a ß-strand-promoting alternating hydrophobic/charged motif, but arrangement of ß-strands into the nanofiber structure has not been previously determined. Here we present a structural model of RADA16-I nanofibers, based on solid-state NMR measurements on samples with different schemes for (13)C isotopic labeling. NMR peak positions and line widths indicate an ordered structure composed of ß-strands. The NMR data show that the nanofibers are composed of two stacked ß-sheets stabilized by a hydrophobic core formed by alanine side chains, consistent with previous proposals. However, the previously proposed antiparallel ß-sheet structure is ruled out by measured (13)C-(13)C dipolar couplings. Instead, neighboring ß-strands within ß-sheets are parallel, with a registry shift that allows cross-strand staggering of oppositely charged arginine and aspartate side chains. The resulting structural model is compared to nanofiber dimensions observed via images taken by transmission electron microscopy and atomic force microscopy. Multiple NMR peaks for each alanine side chain were observed and could be attributed to multiple configurations of side chain packing within a single scheme for intermolecular packing.

Solid-state NMR evidence for ß-hairpin structure within MAX8 designer peptide nanofibers.

MAX8, a designer peptide known to undergo self-assembly following changes in temperature, pH, and ionic strength, has demonstrated usefulness for tissue engineering and drug delivery. It is hypothesized that the self-assembled MAX8 nanofiber structure consists of closed ß-hairpins aligned into antiparallel ß-sheets. Here, we report evidence from solid-state NMR spectroscopy that supports the presence of the hypothesized ß-hairpin conformation within the nanofiber structure. Specifically, our (13)C-(13)C two-dimensional exchange data indicate spatial proximity between V3 and K17, and (13)C-(13)C dipolar coupling measurements reveal proximity between the V3 and V18 backbone carbonyls. Moreover, isotopic dilution of labeled MAX8 nanofibers did not result in a loss of the (13)C-(13)C dipolar couplings, showing that these couplings are primarily intramolecular. NMR spectra also indicate the existence of a minor conformation, which is discussed in terms of previously hypothesized nanofiber physical cross-linking and possible nanofiber polymorphism.

A kind of specific osteolytic destruction of the vertebral bodies.

This report describes two young patients with osteolytic destruction in two adjacent vertebral bodies along with the intervertebral disc, and reveals its possible mechanism. A lateral radiograph and CT scan displayed a giant osteolytic cavity in the L4 vertebral body. An MRI or CT scan with a two-dimensional reconstruction displayed the same changes in the L4 vertebral body and lower endplate erosion in the L3 vertebral body. A comprehensive preoperative evaluation did not identify a specific cause of vertebral destruction. Both patients underwent anterior lumbar fusion surgery. The lesions were removed for histological and immunohistochemical examination. Histopathological study of the destructed vertebral bodies in the two patients revealed the disruption or atrophy of bone trabeculae with infiltration of a large amount of B-lymphocytes and macrophages into the marrow cavities. Studies of its pathogenesis reveal that it is likely to be a B-lymphocyte-mediated local immune inflammatory reaction in the lumbar spine.

Rate constants and mechanisms of intrinsically disordered proteins binding to structured targets.

The binding of intrinsically disordered proteins (IDPs) to structured targets is gaining increasing attention. Here we review experimental and computational studies on the binding kinetics of IDPs. Experiments have yielded both the binding rate constants and the binding mechanisms, the latter via mutation and deletion studies and NMR techniques. Most computational studies have aimed at qualitative understanding of the binding rate constants or at mapping the free energy surfaces after the IDPs are engaged with their targets. The experiments and computation show that IDPs generally gain structures after they are engaged with their targets; that is, interactions with the targets facilitate the IDPs' folding. It also seems clear that the initial contact of an IDP with the target is formed by just a segment, not the entire IDP. The docking of one segment to its sub-site followed by coalescing of other segments around the corresponding sub-sites emerges as a recurring feature in the binding of IDPs. Such a dock-and-coalesce model forms the basis for quantitative calculation of binding rate constants. For both disordered and ordered proteins, strong electrostatic attraction with their targets can enhance the binding rate constants by several orders of magnitude. There are now tremendous opportunities in narrowing the gap in our understanding of IDPs relative to ordered proteins with regard to binding kinetics.